Cardiovascular diseases are the leading cause of death in the US, accounting annually for more than one million death. Atherosclerosis, which forms a part of the cardiovascular abnormalities, is responsible for 50% of all mortality in the USA, Europe and Japan. Atherosclerosis is the principle cause of heart attack, myocardial and cerebral infarction, angina, organ failure, stroke, and gangrene and loss of function in the extremities.
There is widespread agreement that multiple risk factors contribute to atherosclerosis, including: hypertension, elevated total serum cholersterol, high levels of low density lipoprotein (LDL) cholesterol, low levels of high density lipoprotein (HDL) cholesterol, diabetes mellitus, severe obesity, and cigarette smoking. However, only a smaller segment of research has focused on the role of non-lipid factors in the development of atherosclerosis, and modifying lipids has become the major focus of treatment and research. This is due to difficulty of demonstrating advantage on atherosclerotic lesions, thus treatment of atherosclerosis has narrowly focused on directly treating elevated cholersterol levels. Since the comprehensive MRFIT study showed that 40% of death due to coronary heart disease occur in men with total cholesterol of &lt;220 mg/dl, it is obvious that too great an emphasis has been placed on lipid lowering. Indeed, only 30% of patients with atherosclerosis have elevated lipids, strongly indicating that other pathogenic factors are involved.
Since effective prevention and treatment of atherosclerosis has not yet been achieved, considerable effort is been made in defining the etiology and potential treatments of atherosclerosis and its consequences. Despite this effort there are still many unansared questions including how and when atherosclerotic lesions become life-threatening, the best point of intervention, and how to detect and monitor the progression of lesions.
Macrophages form an important part of the host defense system in normal and pathological processes and also participate in the development and the pathogenesis of several diseases, including atherosclerosis. Macrophage scavenger receptors play a key role in atherogenesis by mediating uptake of modified low density lipoprotein (LDL) in arterial walls, and in host defense by binding bacterial endotoxins, bacteria, and protozoa.
The modification of LDL in arterial walls and its subsequent scavenger receptor-mediated uptake into macrophages have been proposed to play a key role in the deposition of lipoprotein cholersterol during the formation of atherosclerosis. The accumulation of lipid-laden foam cells, derived from macrophages and smooth muscle cells (SMC), is one of the characteristic early changes in the arterial intima of a developing atherosclerotic plaque. The process leading to the transformation of macrophages and SMC into foam cells appears to involve the scavenger receptor. A number of in vitro and in vivo studies support this model of atherogenesis. For example, it has been found that after incubation with modified LDL in vitro, CHO cells expressing bovine scavenger receptors can be converted into lipid-laden cells that resemble the macrophages in plaques. Also, scavenger receptor mRNA and protein as well as modified LDL have been detected in atherosclerotic plaques. (For discussion of importance of scavenger receptor in atherosclerotic events see Krieger et al., The Journal of Biological Chemistry, Vol 268, No. 7, pp 4569-4572, 1993, and the references cited therein. Clearly scavenger receptors are important tool to study and eventually treat atherosclerosis and its attendant diseases.
Studies on binding of Ox-LDL (oxidized-LDL) and Ac-LDL (acetylated-LDL) to cells in culture have suggested that a single scavenger receptor type does not account for all of the observed interactions and uptake characteristics. Very recently, a new member of the scavenger receptor family referred to as Marco scavenger receptor (MmarcoSR), has been cloned from a mouse macrophage cDNA library (Eloma et al., Cell, Vol 80, pp 603-609, 1995).
The Marco scavenger receptor has also been implicated in the binding of gram positive and gram negative bacteria but not yeast. The C-terminal domains V and VI of Marco and scavenger receptor show high degree of homology each containing six cysteine residues with similar spacing. This scavenger receptor cysteine-rich motif has been found in a number of other proteins. These proteins are expressed on the surfaces of cells associated with the immune system and host defense functions (T cells, B cells and macrophages) or are secreted and known or suspected of being involved in host defense.
The binding of Marco to bacteria and the expression of this protein in specific macrophage subpopulations indicates that it plays a role in immunological reactions. The marginal zone macrophage of the spleen where Marco is highly expressed form a very special population in many respects. The large macrophages are strategically positioned in the anatomical compartment of the spleen where the blood stream leaves the small arterioles and passes into the so-called open venous system. Here, the phagocytosing system first contacts blood-borne pathogens, and the highly phagocytic marginal zone macrophages. The binding properties and restricted expression of Marco in subpopulations of macrophages that are involved in the uptake of bacterial antigenic polysaccarides indicates that Marco plays important role in the host defense system and homeostasis of the body.
The polypeptides of the present invention have amino acid sequence homology to known murine Marco scavenger receptor (MmarcoSR).